Colorectal cancer afflicts approximately 150,000 Americans and one million people worldwide annually (Cappell, M. S. 2008. Gastroenterol Clin North Am 37:1-24). Progress has been made in understanding its molecular carcinogenesis and in early detection. Surgery, chemotherapy, and radiation have remained the mainstays of therapy. Unfortunately, colorectal cancer remains the second leading cause of death from cancer in the United States, and subject survival has improved only modestly during the past two decades. Therefore, further investigations into novel therapies, such as immunotherapies, are warranted.
Both natural killer (NK) cells and cytotoxic T cells express the NKG2D receptor that can recognize NKG2D ligands (NKG2DLs) (e.g., MICA, MICB and ULBP1-6) on tumor cells (Champsaur, M. & L. L. Lanier. 2010. Immunol Rev 235:267-285; Gonzalez et al. 2008. Trends Immunol 29:397-403). Although the molecular mechanism that regulates NKG2DL expression is not clear, a variety of stimuli, such as oxidation, heat shock, and DNA damage, which induce cell stress and tumor transformation, have been shown to selectively upregulate NKG2DL expression (Gasser et al. 2005. Nature 436:1186-1190; Groh et al. 1996. Proc Natl Acad Sci USA 93:12445-12450; Yamamoto et al. 2001. Biochim Biophys Acta 1526:10-12). During tumor progression, however, most tumor cells eventually acquire various mechanisms such as ligand shedding and microRNA expression that downregulate the surface expression of NKG2DLs, resulting in immunosurveillance escape (Salih, et al. 2002. J Immunol 169:4098-4102; Stern-Ginossar et al. 2008. Nat Immunol 9:1065-1073). In colorectal carcinoma, high expression of NKG2DLs is frequently observed in early stages of tumor development. The ligand expression, however, progressively decreases in later stages of the disease, and this lower level of expression correlates with reduced subject survival (McGilvray et al. 2009. Clin Cancer Res 15:6993-7002). Therefore, studies are needed to elucidate the mechanism of NKG2DL regulation and to identify therapeutic drugs that can upregulate their expression.